NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.
Type
ArticleAuthors
Sengupta, DeepanwitaZeng, Liyong
Li, Yumei
Hausmann, Simone
Ghosh, Debopam
Yuan, Gang
Nguyen, Thuyen N
Lyu, Ruitu
Caporicci, Marcello
Morales Benitez, Ana
Coles, Garry L
Kharchenko, Vladlena
Czaban, Iwona
Azhibek, Dulat
Fischle, Wolfgang

Jaremko, Mariusz

Wistuba, Ignacio I
Sage, Julien
Jaremko, Lukasz

Li, Wei
Mazur, Pawel K
Gozani, Or
KAUST Department
BioscienceBiological and Environmental Science and Engineering (BESE) Division
Bioscience Program
Date
2021-11-04Online Publication Date
2021-11-04Print Publication Date
2021-11Embargo End Date
2022-09-23Submitted Date
2021-05-11Permanent link to this record
http://hdl.handle.net/10754/671927
Metadata
Show full item recordAbstract
The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2$_{E1099K}$, a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.Citation
Sengupta, D., Zeng, L., Li, Y., Hausmann, S., Ghosh, D., Yuan, G., … Gozani, O. (2021). NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis. Molecular Cell, 81(21), 4481–4492.e9. doi:10.1016/j.molcel.2021.08.034Sponsors
We thank members of the Gozani and Mazur labs for critical reading of the manuscript. This work was supported in part by grants from the NIH (R35 GM139569 to O.G., R01 CA236118 to O.G. and P.K.M., K99 CA255936 to S.M., and R01HG007538, R01CA193466, and R01CA228140 to W.L.); intramural funds from KAUST (to W.F., L.J., and M.J.); and AACR, NETRF, a DOD PRCRP career development award (CA181486), a career enhancement grant from The University of Texas NIH SPORE in Lung Cancer (P50CA070907), and the Andrew Sabin Family Foundation Scientist and CPRIT Scholar in Cancer Research (RR160078) (to P.K.M.). D.S. was supported by a grant from the Stanford Maternal and Child Health Research Institute. This work was also supported in part by the Stanford Cancer Institute, a NCI-designated Comprehensive Cancer Center.Journal
Molecular cellPubMed ID
34555356ae974a485f413a2113503eed53cd6c53
10.1016/j.molcel.2021.08.034
Scopus Count
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